Field of the Invention
The present invention generally relates to copper-catalyzed radiofluorination of iodonium salts, to iodonium salts and compounds obtained by copper-catalyzed radiofluorination of iodonium salts, and to diagnostic and therapeutic methods involving such compounds.
Brief Description of Related Technology
Positron emission tomography (PET) is a powerful and minimally invasive medical imaging technique that provides kinetic physiochemical information. The most commonly used radioisotope for PET is 18F, which offers the advantages of high resolution imaging (ca. 2.5 mm in tissue), a relatively long lifetime (t1/2=110 min), and minimal perturbation of radioligand binding. Despite these advantages, the development of novel 18F radiotracers is currently impeded by a paucity of general and effective radiofluorination methods. There are currently few robust synthetic procedures for the incorporation of 18F into organic molecules with sufficient speed, selectivity, yield, radiochemical purity, and reproducibility to provide clinical imaging materials. Direct methods for the late stage nucleophilic [18F]fluorination of electron-rich aromatic substrates remains an especially long-standing challenge in the PET community. A target of particular interest in this regard is 6-[18F]fluoro-L-DOPA (6-[18F]fluoro-L-3,4-dihydroxyphenylalanine), which serves as a valuable diagnostic for probing the regional distribution of dopamine in the human brain. While there has been much activity in the radiofluorination community aimed at accessing 6-[18F]fluoro-L-DOPA, current methods suffer from drawbacks (including low specific activity, multi-step procedures, chiral separations, and/or poor yield) that limit routine production of this material.
The majority of radiofluorination methods for electron rich aryl rings utilize electrophilic fluorinating reagents derived from [18F]F2. However, [18F]F2 production typically requires 19F2 as a carrier gas, which leads to low specific activity (SA) radiotracers (typically <1.0 Ci/mmol) and requires specialized facilities. The development of [18F]KF production from [18O]water has provided the means to synthesize high SA radiotracers (>1,000 Ci/mmol) through nucleophilic substitution (typically SN2 or SNAr). However, the use of [18F]KF is generally limited to the formation of primary sp3-C—F bonds or sp2-C—F bonds on activated electron deficient aromatics.
Two main strategies have been used to address these limitations. The first involves radiofluorination of powerful electrophiles such as diaryliodonium salts. Diaryliodonium salts bearing the 2-thienyl group have been shown to react with [18F]KF at elevated temperatures (often ≥150° C.) to afford [18F]fluoroarenes (Scheme 1). In these systems, the 2-thienyl group directs radiofluorination to the other aromatic ligand on iodine, with moderate to good selectivity. However, the [(thienyl)(aryl)I+] starting materials are often challenging to prepare, suffer from low stability, and have a limited shelf-life. Furthermore, with electron neutral or rich substrates, these transformations frequently require high temperatures, exhibit modest regioselectivity, demonstrate limited functional group tolerance, and provide low radiochemical yields. As such, it has proven challenging to access important radiotracers, most notably 6-[18F]fluoro-L-DOPA derivatives, using this method.

A second strategy applies transition metal catalysts and/or reagents to achieve nucleophilic radiofluorination. Transition metal catalysis offers opportunities for accelerating radiofluorination reaction rates as well as enhancing selectivity and reactivity. For instance, progress has been made in nucleophilic radiofluorination using Pd (Lee, E., Science 334:639 (2011); Kamlet, A. S., PLoS One 8:e59187 (2013)) and Ni (Lee, E., J. Am. Chem. Soc. 134:17456 (2012)) complexes. However, the requirement for the multistep synthesis of organometallic reagents under inert atmospheres has thus far limited adoption of these methods by non-experts.
Fluorination reactions disclosed in WO 2010/048170 also suffer from various deficiencies.
The present invention provides a general, mild, high-yielding, and user-friendly procedure for the radiofluorination of diverse aromatic substrates by merging transition metal catalysis with the fluorination of diaryliodonium salts.